The HIV envelope protein, gp120, mediates entry of viral particles into CD4+ T cells. Gp120 binds to the CD4 receptor and a co-receptor, either CCR5 or CXCR4. These receptors are expressed on a subset of human lymphocytes and macrophages, and thus it is these cells that are productively infected by HIV. Because gp120 is the only viral protein against which neutralizing antibodies are elicited, it is a primary target of therapeutic agents designed to block infection of human cells by HIV, and a key component of a potential AIDS vaccine. Gp120 is also recognized by C-type lectin receptors, and other yet unidentified receptors. We have focused our recent efforts on the interaction between gp120 and an unidentified receptor expressed on the surface of natural killer (NK) cells. NK cells play a central role in innate immune responses against foreign pathogens. NK cells obtained from HIV-infected individuals exhibit profound functional defects in vitro. They fail to lyse target cells efficiently, and have a reduced capacity to secrete interferon gamma. To investigate the mechanism of these defects we identified the receptor on NK cells that binds to gp120. We have determined that gp120 binding to NK cells is mediated by alpha4beta7 integrin. Not only is this integrin expressed on NK cells, but it is also expressed on subsets of CD4+ and CD8+ T-cells. Because alpha4beta7 is the principal integrin involved in lymphocyte homing to the lamina propria of gut associated lymphoid tissue (GALT), and the primary targets of HIV are CD4+ T-cells localized to lymphoid tissues, particularly GALT, our observations suggest that the direct interaction between HIV gp120 and alpha4beta7 provides a plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT.[unreadable] [unreadable] Gp120-binding to alpha4beta7 is mediated by an LDV peptide sequence in its V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, which are the natural ligands for alpha4beta7. Removal of this sequence in the HIV envelope abrogates binding to alpha4beta7 integrin. A prototypical alpha4beta7 peptide antagonist based on the LDV sequence inhibits gp120 binding to alpha4beta7 integrin. This suggests that many of the alpha4 integrin antagonists that are currently in clinical development will also inhibit this interaction. Our current work is focused on the role of alpha4beta7 integrin in HIV replication, transmission and pathogenesis.